Obesity is a huge and increasing medical problem, with inadequate therapeutic options. One approach to the treatment of obesity is long-term pharmacotherapy. One modestly effective drug, orlistat, has been marketed in the United States since 1999. More recently other drugs have been approved by the FDA: lorcaserin and Qsymia (a combination of phentermine and topiramate) in 2012 and Contrave (a combination of buproprion and naltrexone) and liraglutide (high dose) in 2014. The limited efficacy of single agents has led to the idea that additional agents and combination therapy are required. Progress in FY2015 includes the following: In 2014 we published a re-examination of chemical uncoupler 2,4-dinitrophenol (DNP) as a treatment for obesity in mice. DNP was an effective and widely used weight loss drug in the early 1930s. DNP treatment increased energy expenditure but did not change food intake. DNP-treated mice weighed 26% less than controls after 2 months of treatment due to decreased fat mass, without a change in lean mass. DNP improved glucose tolerance and reduced hepatic steatosis without observed toxicity. DNP treatment also reduced brown adipose tissue activity, demonstrating that DNP-mediated heat generation substituted for brown adipose tissue thermogenesis. At 22 C, a typical vivarium temperature that is below thermoneutrality, DNP treatment had no effect on body weight, adiposity, or glucose homeostasis. Thus, environmental temperature should be considered when assessing an anti-obesity drug in mice, particularly agents acting on energy expenditure. Furthermore, the beneficial effects of DNP suggest that chemical uncouplers deserve further investigation for the treatment of obesity and its comorbidities. This year, we reported the effects of CL316243, a beta3-adrenergic agonist studied under similar conditions. To our surprise, the interaction between environmental temperature and CL316243 treatment is different from the interaction between environmental temperature and 2,4-dinitrophenol treatment reported previously, suggesting that each drug mechanism must be examined to understand the effect of environmental temperature on drug efficacy.